Underappreciated Opportunities for High-Density Lipoprotein Particles in Risk Stratification and Potential Targets of Therapy

Abstract

The inverse relationship between high-density lipoprotein cholesterol (HDL-C) concentrations and coronary heart disease risk is well established. As a result, in recent years there have been significant resources focused on identifying therapies that raise HDL-C and ultimately reduce cardiovascular events. Unfortunately, a number of trials aimed at increasing HDL-C have failed to show improved outcomes, and hence, have cast doubt on the importance of HDL-C as a therapeutic target. HDL-C, however, is only one measure of HDL. HDL levels can also been estimated by quantifying apolipoprotein A-I (apoA-I) levels using enzyme immunoassay or by measuring HDL particle number (HDL-P) using nuclear magnetic resonance spectroscopy (NMR) or ion mobility. While these surrogate measures are correlated, they are not comparable. Lipoprotein-altering therapies have been shown to have different effects on HDL-C, apoA-I and HDL-P and several studies have demonstrated that HDL-P is a stronger predictor of coronary heart disease risk than HDL-C and/or apoA-I. This paper will review available evidence supporting the use of HDL-P as the biomarker of choice to assess the contribution of HDL to cardiovascular risk and as the primary goal of HDL-raising therapies.

Effect of Switching From Statin Monotherapy to Ezetimibe/Simvastatin Combination Therapy Compared With Other Intensified Lipid‐Lowering Strategies on Lipoprotein Subclasses in Diabetic Patients With Symptomatic Cardiovascular Disease

“…The changes in HDL‐P observed when the patients were switched to rosuvastatin (10 mg/day) were less dependent on changes in the concentration of large HDL‐P. It remains unclear whether changes in the concentrations of any specific HDL subpopulations are more important in risk reduction than overall changes in HDL‐P number 55, 56, 57…”

New Challenges for HDL-Modifying Therapies as a Strategy to Lower Cardiovascular Disease Events in Statin-Treated Patients

“…Since ABCA1 is the essential pathway that mediates macrophage cholesterol efflux, and high potency statin therapy is evidence-based and guideline recommended therapy for high cardiovascular risk patients, Thus, the implications of this current report [15] may represent one source of residual cardiovascular risk in statin-treated patients. Interestingly, increased expression of hepatic miRNA33 [16] may be one explanation for the dose-dependent reduction in HDL cholesterol levels observed with atorvastatin [17] and differences in HDL cholesterol and HDL particle concentration reported with equipotent LDL cholesterol lowering doses of atorvastatin and rosuvastatin [6].…”

“…Among high-risk individuals treated with high-intensity statin therapy, low HDL-C has not been a consistent biomarker of cardiovascular events [5,6]. In the Treating to New Targets (TNT) trial, atorvastatin-treated patients who achieved low density lipoprotein (LDL) cholesterol levels less than 70 mg/dL, recurrent cardiovascular events were higher among subgroups with low HDL cholesterol levels [7].…”

“…Low HDL cholesterol is also considered a biomarker of elevated triglyceride-rich lipoproteins as shown in Mendelian randomization studies [9]. In contrast to HDL cholesterol, HDL particle number is more strongly associated with increased cardiovascular risk in statin-treated individuals [6]. In JUPITER, a primary prevention trial of individuals at high risk for an initial cardiovascular event, on-trial levels of HDL cholesterol were not associated with cardiovascular risk in rosuvastatin-treated individuals [10].…”

Meal-Induced Oxidative Stress

“…While elevated HDL is commonly associated with lower CHD risk in both men and women [7], there is better understanding of the impact of HDL heterogeneity on its quantity, quality and function [8]. While one of the key anti-atherogenic properties of HDL is its ability to protect LDL from oxidative modification, in certain metabolic conditions, HDL may actually act as a pro-oxidant and pro-inflammatory agent [9,10].…”